反义lncRNA gsk3βAS3调控GSK-3β影响抑郁的机制研究

神经可塑性障碍是抑郁症的核心病理机制之一，其中最重要的因素是神经营养转导通路异常。既往及本课题组系列研究表明GSK-3β是该通路的关键分子，其表达/活性异常与抑郁症的发生发展密切相关，但对GSK-3β的调控机制仍未阐明。课题组前期筛选工作发现抑郁症异常表达的lncRNAs中89%为反义RNA，并进一步观察到抑郁症治疗前后外周血中反义lncRNA-gsk3βAS3表达明显异常，细胞实验提示抑制其表达后显著影响GSK-3β的表达及活性。基于lncRNA-gsk3βAS3与GSK-3β在基因组的毗邻关系，提出以下假说：lncRNA-gsk3βAS3通过抑制GSK-3β参与抑郁的发生发展。本课题拟采用分子、动物、人体多水平研究验证：1.gsk3βAS3调控GSK-3β表达；2.gsk3βAS3影响GSK-3β参与抑郁的发生发展。其成果有望为抑郁症神经可塑障碍的病理机制及抗抑郁药物的研发提供新线索。

It has been recognized that the aberrant signal transduction pathway in neurons may result in the disorder of neuroplasticity and likely to be involved in the pathophysiology of Major Depressive Disorder (MDD). Glycogen synthesis kinase-3β(GSK-3β) is vital on this pathway. Our previous series studies have shown that the altered expression and activity of GSK-3β contribute to the pathophysiology of MDD. Furthermore, in our preliminary study, we identified aberrantly expressed circulating lncRNAs in MDD patient by gene chip screening. The results indicate that 89% of them were antisense RNA. Specially, we found that an antisense lncRNA gsk3βAS3 in the peripheral blood was up-regulated expression in the MDD patient. Interestingly, it was greatly reduced after drug treatment, and the down-regulated GSK-3β mRNA and serine-9 phosphorylated GSK-3β levels after lenti-sh lncRNA gsk3βAS3 infection in the NPC cells. Due to adjacent genomic loci relationship between lncRNA-gsk3βAS3 and GSK-3βwas considered as a regulating partner, we proposed a hypothesis that lncRNA-gsk3βAS3 participates in the pathogenesis of depression through regulating GSK-3β. To address this hypothesis, we will focus on verification of (1) lncRNA-gsk3βAS3 suppressing the expression of GSK-3β; (2) lncRNA-gsk3βAS3 participating in the formation and development of depression by regulating GSK-3βon a multiple level of molecular, cellular and whole body of both animal and human. This outcome may provide a new insight regarding the mechanism of neuroplasticity disorder in MDD and the exploration for new antidepressant.